Cysteine prodrugs to treat schizophrenia and drug addiction

ABSTRACT

The present invention provides cysteine prodrugs for the treatment of schizophrenia and drug addiction. The invention further encompasses pharmaceutical compositions containing prodrugs and methods of using the prodrugs and compositions for treatment of schizophrenia and drug addiction.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. application Ser. No.12/189,516, filed on Aug. 11, 2008, which claims the benefit of U.S.Application No. 60/955,269, filed Aug. 10, 2007. Both applications areincorporated by reference herein in their entirety.

FIELD OF THE INVENTION

This invention relates generally to the treatment of schizophrenia anddrug addiction. More particularly, the present invention is directed tocysteine prodrugs useful as antipsychotic medications in the treatmentof schizophrenia. As well, the respective prodrugs are applicable forreducing drug cravings in drug addicted individuals.

BACKGROUND OF THE INVENTION

Schizophrenia is a debilitating disorder afflicting 1% of the world'spopulation. The development of effective medications to treatschizophrenia is reliant on advances in characterizing the underlyingpathophysiology. Chlorpromazine and other phenothiazines are consideredfirst generation antipsychotics (termed “typical antipsychotics”) usefulin the treatment of schizophrenia. However, the antipsychotic efficacyof phenothiazines was, in fact, serendipitously discovered. These drugswere initially used for their antihistaminergic properties and later fortheir potential anesthetic effects during surgery. Hamon and colleaguesextended the use of phenothiazines to psychiatric patients and quicklyuncovered the antipsychotic properties of these compounds; shortlythereafter, the pharmacologic characteristic of dopamine receptorblockade was linked to the antipsychotic action of chlorpromazine(Thorazine). This led to the development of additional dopamine receptorantagonists, including haloperidol (Haldol). For nearly fifty years,dopamine antagonists were the standard treatment for schizophrenia eventhough these drugs induce severe side effects ranging from Parkinson'sdisease-like motor impairments to sexual dysfunction and are onlyeffective in treating the positive symptoms of schizophrenia.

In the 1970's, clozapine became the first “atypical psychotic” or 2ndgeneration antipsychotic agent introduced. Clinical trials have shownthat clozapine produces fewer motor side effects and exhibits improvedefficacy against positive and negative symptoms relative to 1stgeneration compounds. However, clozapine was briefly withdrawn from themarket because of the potential to produce severe agranulocytosis, apotentially fatal side effect requiring patients to undergo routine,costly hematological monitoring. As a result, clozapine is only approvedfor treatment-resistant schizophrenia. Although also a dopamine receptorantagonist, the therapeutic site of action for clozapine is thought toinvolve, at least in part, blockade of serotonin receptors. This led tothe generation of other serotonin receptor antagonists in the 1990'swith the goal of improving the safety profile of clozapine.

The growth potential for novel antipsychotics was revealed following theintroduction of risperidone in 1994; within two years risperidoneovertook haloperidol in the number of prescriptions written byphysicians. While it was generally assumed that the newer 2nd generationantipsychotics also exhibited the favorable efficacy profile produced byclozapine, the clinical data was ambiguous. As a result, the NIHrecently funded a large, lengthy, and expensive clinical trial toexamine this assumption. The results of the Clinical AntipsychoticTrials of Intervention Effectiveness (CATIE), recently released,indicate that there is no benefit to the newer 2nd generation compounds.Specifically, 1st and 2nd generation drugs did not differ in theincidence of severe motor side-effects nor were 2nd generation agentsfound to be more effective than 1st generation antipsychotics. In theCATIE trial, 74% of the patients discontinued treatment prior tocompleting the 18 month trial, in part due to a lack of efficacy andintolerability of the treatment regimen.

Uncontrolled drug use and heightened susceptibility to relapse aredefining features of addiction that contribute to the transition in drugconsumption from a recreational to a compulsive pattern. Long-termplasticity resulting in augmented excitatory neurotransmission withincorticostriatal pathways in response to drugs of abuse have beenimplicated in addiction. Human cocaine abusers exposed tocraving-inducing stimuli exhibit increased activation of excitatorycircuits originating in cortical regions, including orbital andprefrontal cortex, and projecting to the ventral striatum; further, thedegree of activation of corticostriatal pathways correlates with cravingin humans. Preclinical data also indicate the existence of drug-inducedplasticity leading to increased activation of corticostriatal pathwaysfollowing exposure to drugs or drug-paired cues. Activation of thesecircuits results in heightened extracellular glutamate in the nucleusaccumbens and stimulation of ionotropic glutamate receptors, both ofwhich are necessary for cocaine primed reinstatement. Further, thedorsomedial prefrontal cortex has been shown to be necessary forreinstatement produced by exposure to drug-paired cues using thecontextual reinstatement paradigm and in response to electrical footshock. As a result, identification of cellular mechanisms capable ofregulating synaptic glutamate represent targets in the treatment ofaddiction.

As can be appreciated from the foregoing, there exists a pressing needand considerable market potential for novel antipsychotic and anti-drugcraving agents. Of course, the development of such agents will befacilitated by a thorough understanding of pathophysiologies underlyingthe neurological disorders.

SUMMARY OF THE INVENTION

The present invention is based on the inventors' success in identifyingderivatives of cysteine with demonstrated utility as antipsychotic andanticraving agents. Accordingly, the present invention provides cysteineprodrugs having the structure:

-   -   a cystine dimer of the prodrug having the structure:

wherein: R¹, R², R⁴ and R⁵ are independently selected from OH, ═O, or abranched or straight chain C₁ to C₅ alkoxyl group, with the caveats thatwhen ═O is selected the nitrogen atom adjacent the carbonyl group thuslyformed bears a H and a single bond joins the adjacent nitrogen to thecarbonyl group and further R¹, R², R⁴ and R⁵ shall be selected to notall be ═O; and R³ is H, a branched or straight chain C₁ to C₅ alkyl, anitrobenzenesulfonyl, an aryl thio, an aryl, an alkylthio, an acyl, abenzoyl, a thio acyl, a thio benzoyl, or a benzyl group.

Certain preferred prodrugs according to the invention have formulas inwhich R¹, R², R⁴ and R⁵ are independently selected from the branched orstraight chain C₁ to C₅ alkoxyl group. Yet other preferred prodrugsaccording to the invention have formulas in which R¹, R², R⁴ and R⁵ areselected from the same branched or straight chain C₁ to C₅ alkoxylgroup. One particularly preferred cysteine prodrug according to theinvention has the structure:

Cysteine prodrugs according to the invention are further provided in theform of cystine dimers, a particularly preferred dimer having thestructure:

In certain embodiments, the invention encompasses pharmaceuticalcompositions comprising a cysteine prodrug or dimer thereof as describedand claimed herein in combination with a pharmaceutically-acceptablecarrier.

In another aspect, the invention is directed to a method of reducingschizophrenia in a subject. Such a method includes steps ofadministering to the subject an effective amount of a cysteine prodrugor dimer thereof, whereby schizophrenia is reduced in the subject.Administration of the cysteine prodrug or dimer is preferablyaccomplished by oral delivery.

In yet another aspect, the invention encompasses a method of reducingdrug craving in a subject. Such a method includes steps of administeringto the subject an effective amount of a prodrug or dimer, whereby drugcraving is reduced in the subject.

Preferred prodrugs for use in treatment methods according to theinvention include the prodrug having the structure:

A preferred prodrug in dimer form for use in the inventive methods isthe cystine dimer having the structure:

The invention also provides a method of reducing schizophrenia in asubject comprising administering to the subject an effective amount of acysteine prodrug having the structure:

-   -   a cystine dimer of the prodrug having the structure:

wherein R is H, a branched or straight chain C₁ to C₅ alkyl, anitrobenzenesulfonyl, an aryl thio, an aryl, an alkylthio, an acyl, abenzoyl, a thio acyl, a thio benzoyl, or a benzyl group, wherebyschizophrenia is reduced in the subject. The preferred route ofadministration is by oral delivery.

In certain methods of reducing schizophrenia, the cysteine prodrugadministered to the subject has the structure:

In another aspect, the invention is directed to a method of reducingdrug craving in a subject comprising administering to the subject aneffective amount of a cysteine prodrug having the structure:

-   -   a cystine dimer of the prodrug having the structure:

wherein R is H, a branched or straight chain C₁ to C₅ alkyl, anitrobenzenesulfonyl, an aryl thio, an aryl, an alkylthio, an acyl, abenzoyl, a thio acyl, a thio benzoyl, or a benzyl group, whereby drugcraving is reduced in the subject. The preferred route of administrationis by oral delivery.

In certain methods of reducing drug craving, the cysteine prodrugadministered to the subject has the structure:

Other objects, features and advantages of the present invention willbecome apparent after review of the specification, claims and drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts a bar graph indicating an increase in extracellularglutamate in the prefrontal cortex (relative to baseline) is greaterfollowing administration of compound 7 shown in Scheme 1 (30 mg/kg, po;N=1;) than cysteine prodrug N-acetylcysteine (60 mg/kg, IP; N=4).

FIG. 2 provides a bar graph demonstrating inhibition of a startleresponse in response to a load stimulus (pulse; 110 db above background)when preceded by a pre-pulse stimulus (2-15 db above background). Thesedata reflect sensorimotor gating because the detection of the prepulse,which signals the oncoming pulse, enables the rat to minimize the normalstartle response in response to the pulse stimulus. Rats pretreated withphencyclidine only (PCP; 1 mg/kg, SC; N=5) failed to exhibit a reductionin the response elicited by the pulse even when preceded by thepre-pulse. Rats pretreated with N-acetylcysteine (30 mg/kg, po; N=5) 60min prior to phencyclidine administration exhibited a trend towardimproved sensorimotor gating (p=0.1). Rats pretreated with compound 7(Scheme 1), (30 mg/kg, po; N=4) exhibited a significant improvement insensorimotor gating relative to PCP controls and rats receiving NAC+PCP(Fisher LSD, p<0.05).

FIG. 3 depicts a bar graph illustrating the impact of N-acetylcysteineadministered orally on deficits in prepulse inhibition produced byphencyclidine.

FIG. 4 shows a bar graph demonstrating the impact of N-acetylcysteinewhen administered into the intraperitoneal cavity of rodents in order tocircumvent hepatic metabolism.

FIG. 5 provides a bar graph showing the impact of N-acetylcysteineinfused directly into the rodent prefrontal cortex, the regionunderlying sensorimotor gating. The improved effect obtained withn-acetylcysteine when infused into the prefrontal cortex relative tooral or IP administration illustrate the problems associated with thepharmacokinetics of N-acetylcysteine.

FIG. 6 depicts a bar graph illustrating the impact of compound 5(Scheme 1) on PCP-evoked deficits in pre-pulse inhibition following oraldelivery in rodents.

FIG. 7 depicts a bar graph illustrating the impact of compound 6(Scheme 1) on PCP-evoked deficits in pre-pulse inhibition following oraldelivery in rodents.

FIG. 8 provides a bar graph illustrating that N-acetylcysteine (IP) iseffective in producing a significant reduction in cocaine-inducedreinstatement at the doses of 30 and 60 mg/kg.

FIG. 9 depicts a bar graph illustrating that N-acetylcysteine is lesseffective when given orally. Further, administration of 1 mg/kg ofCompound 5 (Scheme 1) was sufficient to block cocaine-inducedreinstatement, an effect that was comparable to 30 mg/kg NAC.

DETAILED DESCRIPTION OF THE INVENTION

Before the present materials and methods are described, it is understoodthat this invention is not limited to the particular methodology,protocols, materials, and reagents described, as these may vary. It isalso to be understood that the terminology used herein is for thepurpose of describing particular embodiments only, and is not intendedto limit the scope of the present invention which will be limited onlyby the appended claims.

It must be noted that as used herein and in the appended claims, thesingular forms “a”, “an”, and “the” include plural reference unless thecontext clearly dictates otherwise. As well, the terms “a” (or “an”),“one or more” and “at least one” can be used interchangeably herein. Itis also to be noted that the terms “comprising”, “including”, and“having” can be used interchangeably.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meanings as commonly understood by one of ordinary skillin the art to which this invention belongs. Although any methods andmaterials similar or equivalent to those described herein can be used inthe practice or testing of the present invention, the preferred methodsand materials are now described. All publications and patentsspecifically mentioned herein are incorporated by reference for allpurposes including describing and disclosing the chemicals, cell lines,vectors, animals, instruments, statistical analysis and methodologieswhich are reported in the publications which might be used in connectionwith the invention. All references cited in this specification are to betaken as indicative of the level of skill in the art. Nothing herein isto be construed as an admission that the invention is not entitled toantedate such disclosure by virtue of prior invention.

In the embodiments described herein and unless indicated otherwise, theterm “alkyl” shall mean a straight or branched, substituted orunsubstituted alkyl group having 1-5 carbon atoms. By “cycloalkyl” it ismeant a ring compound containing 3-7 carbon atoms. Also, the term“aromatic” refers to cyclic or heterocyclic compounds displayingaromaticity. As used herein, the term “alkoxyl” group refers to an alkyl(as defined above) group linked to oxygen to provide the generalchemical moiety —OR.

As used herein, the term “administering” refers to bringing a subject,tissue, organ or cells in contact with the cysteine prodrugs describedin this disclosure. In certain embodiments, the present inventionencompasses administering the compounds useful in the present inventionto a patient or subject. A “subject”, “patient” and “individual”, usedequivalently herein, refers to a mammal, preferably a human, thateither: (1) has a disorder remediable, treatable, or diminished inseverity by administration of cysteine prodrugs and dimers thereofaccording to the invention; or (2) is susceptible to a disorder that ispreventable by administering same.

As used herein, the terms “effective amount” and “therapeuticallyeffective amount” refer to the quantity of active therapeutic agentssufficient to yield a desired therapeutic response without undue adverseside effects such as toxicity, irritation, or allergic response. Thespecific “effective amount” will, obviously, vary with such factors asthe particular condition being treated, the physical condition of thepatient, the duration of the treatment, the nature of concurrent therapy(if any), and the specific formulations employed. In this case, anamount would be deemed therapeutically effective if it resulted in oneor more of the following: (a) the prevention of schizophrenia and/ordrug craving; and (b) the reduction or stabilization of schizophreniaand/or drug craving. The optimum effective amounts can be readilydetermined by one of ordinary skill in the art using routineexperimentation.

The present inventors have recently identified the cystine-glutamateantiporter as a highly novel cellular process that likely contributes tothe pathology underlying schizophrenia and drug addiction. Importantly,the inventors have collected the first data set indicating that cysteineprodrugs, used to increase the activity of cystine-glutamateantiporters, block cognitive deficits and social withdrawal in thepreclinical phencyclidine model of schizophrenia. Unlike existingmedications, cysteine prodrugs appear to exert antipsychotic properties,in part, by reversing pathology underlying the disease.

While no one theory or mechanism of pharmacological effect is adoptedherein, cysteine prodrugs appear to restore diminished signaling toglutamate receptors and diminished glutathione levels observed inschizophrenics. A depleted glutathione level can lead to increasedoxidative stress, and impaired cystine-glutamate antiporter activity,glutamate neurotransmission, synaptic connection, and gene expression,all of which are observed in schizophrenia.

Increased excitatory neurotransmission in the nucleus accumbens mayarise, in part, by diminished activity of cystine-glutamate antiporters.The recent data collected by the present inventors illustrates thatglutamate released from these antiporters provides endogenous tonicstimulation to group II or 2/3 metabotropic glutamate receptors(mGluRas) and thereby regulates synaptic glutamate and dopamine release.Thus, altered glutamate signaling could arise as a consequence ofdecreased cystine-glutamate exchange. Repeated cocaine administrationhas been shown to blunt the activity of cystine-glutamate exchange,which likely contributes to a sequence of events, including diminishedgroup II mGluR autoregulation and increased excitatory neurotransmissionin the nucleus accumbens.

Impaired cystine-glutamate antiporter activity and faulty glutamateneurotransmission bear on the issue of uncontrolled drug use, i.e., drugaddiction. Cysteine prodrugs, such as N-acetylcysteine (“NAC”), are usedto drive cystine-glutamate exchange by apparently elevatingextracellular cystine levels, thereby creating a steep cystineconcentration gradient. Preclinical studies have shown N-acetylcysteineto be effective in blocking compulsive drug-seeking in rodents. Further,extant clinical data also show a reduction in cocaine use and craving incocaine abusers receiving NAC. Unfortunately, the full clinical efficacyof targeting cystine-glutamate exchange may be unrealized when utilizingNAC due to extensive first-pass metabolism and limited passive transportof this drug across the blood-brain barrier. The prodrugs described andclaimed herein are not significantly eliminated by the liver and willreadily pass the blood-brain barrier. Cysteine is the reduced form ofcystine and is readily oxidized in vivo to cystine, thus elevatingeither cysteine or cystine is believed to increase cystine-glutamateexchange.

The cysteine prodrug NAC has been previously shown to have a favorablesafety/tolerability profile in human subjects. In fact, NAC has beenused for decades in humans for other indications (e.g., as a mucolytic,acetaminophen toxicity) and as an experimental treatment (HIV, cancer)without producing severe adverse effects. However, NAC undergoesextensive first pass metabolism requiring the usage of high doses thatlimit the utility of the drug and, potentially, increase the chances ofside effects due to the buildup of metabolized by-products. The prodrugspresently disclosed and claimed herein are designed to substantiallyavoid the problem of first pass metabolism and poor blood brain barrierpermeability, and therefore exhibit increased efficacy as compared toprior cysteine prodrugs as illustrated by improved potency and/orefficacy.

Repeated cocaine alters glutamate neurotransmission even followingprotracted withdrawal, and this likely contributes to addiction sinceabnormal activation of corticostriatal pathways correlates with cravingin humans and is necessary for cocaine seeking in rodents. Revealingcellular mechanisms underlying altered corticostriatal activation shouldadvance our understanding of the neurobiological basis of addiction andidentify novel therapeutic targets.

Models of pathological glutamate signaling proposed to underlieaddiction need to account for the existence of multiple pools ofextracellular glutamate. Aside from synaptic glutamate maintained byvesicular release, extrasynaptic glutamate is sustained primarily bynonvesicular release. In support, basal extrasynaptic glutamate sampledusing microdialysis are largely independent of vesicular glutamate.Glutamate transporters may partition the two pools by limiting glutamateoverflow from the synapse into extrasynaptic compartments, andrestricting entry of nonvesicular glutamate into synapses. Althoughconfined to the extrasynaptic compartment, nonvesicular glutamateregulates neurotransmission by stimulating group II metabotropicglutamate receptors (mGluRs) which are extrasynaptic receptors capableof inhibiting vesicular release. Thus, extrasynaptic receptors permitcrosstalk between the two pools and indicate that altered nonvesicularglutamate release may contribute to pathological glutamate signalinglinked to addiction.

Cystine-glutamate exchange via the cystine/glutamate transporter systemmay be critical in the capacity of extrasynaptic glutamate to regulatecorticostriatal signaling in the normal and pathological states. First,nonvesicular release from cystine-glutamate exchange maintains basalextracellular glutamate in the nucleus accumbens, and thereby regulatesthe extent of endogenous group II mGluR stimulation. Repeated cocaineblunts transporter activity which leads to reduced basal and increasedcocaine-evoked glutamate in the nucleus accumbens that persists for atleast three weeks after the last cocaine treatment. These changes arerelevant for drug seeking since N-acetylcysteine, a cysteine prodrugused to drive the transporter system, blocks cocaine-evoked glutamate inthe nucleus accumbens and subsequent cocaine-induced reinstatement.

Depicted below in Scheme 1 is the general synthetic route formanufacturing cysteine prodrugs and dimers according to the invention,including specific prodrugs 4 and 5 which are exemplary chemicalentities useful in the invention. Exemplary cystine dimers joined bydisulfide linkages and corresponding to prodrugs 4 and 5 are illustratedas compounds 7 and 6, respectively. The chemistry employed in themanufacture of prodrugs according to the invention is adapted, in part,on Scholkopf chiral auxiliary chemistry described in the literature(indicated by a superscript ^(c)throughout Scheme 1; see, e.g., Zhao, S.et al.). Example 1 of this disclosure provides additional detaileddescription of the chemical syntheses of Scheme 1.

Further referring to Scheme 1, compounds 8a and 8b represent partiallyalkylated derivatives of respective compound 5, effectivelyintermediates between compound 5 and compound 4 as compound 5 undergoesmetabolism to yield compound 4 following administration of compound 5 toa subject. Likewise, compounds 9a and 9b represent partially alkylatedderivatives of respective compound 6, effectively intermediates betweencompound 6 and compound 7 following administration of compound 6 to asubject. As can be appreciated, compounds 8a, 8b, 9a, 9b and similarpartially alkylated versions of compounds according to the invention canthemselves serve as cysteine prodrugs and may therefore be administeredby the methods described and claimed herein.

Upon administration to a subject, prodrugs and dimers according to theinvention pass largely intact through first pass metabolism other thanthe hydrolysis reactions shown in Scheme 1. Such prodrugs and dimers areeventually cleaved into the corresponding amino acids by peptidases incells contained within the central nervous system (CNS).

Accordingly, the present invention is directed to cysteine prodrugshaving the structure:

-   -   a cystine dimer of the prodrug having the structure:

wherein: R¹, R², R⁴ and R⁵ are independently selected from OH, ═O, or abranched or straight chain C₁ to C₅ alkoxyl group, with the caveats thatwhen ═O is selected the nitrogen atom adjacent the carbonyl group thuslyformed bears a H and a single bond joins the adjacent nitrogen to thecarbonyl group and further R¹, R², R⁴ and R⁵ shall be selected to notall be ═O; and R³ is H, a branched or straight chain C₁ to C₅ alkyl, anitrobenzenesulfonyl, an aryl thio, an aryl, an alkylthio, an acyl, abenzoyl, a thio acyl, a thio benzoyl, or a benzyl group.

Certain preferred prodrugs according to the invention have formulas inwhich R¹, R², R⁴ and R⁵ are independently selected from the branched orstraight chain C₁ to C₅ alkoxyl group. Yet other preferred prodrugsaccording to the invention have formulas in which R¹, R², R⁴ and R⁵ areselected from the same branched or straight chain C₁ to C₅ alkoxylgroup. One particularly cysteine prodrug according to the invention hasthe structure:

Cysteine prodrugs according to the invention are further provided in theform of cystine dimers, a particularly preferred dimer having thestructure:

In certain embodiments, the inventive compounds will be provided aspharmaceutically acceptable salts. Other salts may, however, be usefulin the preparation of the compounds according to the invention or oftheir pharmaceutically acceptable salts. Suitable pharmaceuticallyacceptable salts of the compounds of this invention include acidaddition salts which may, for example, be formed by mixing a solution ofthe compound according to the invention with a solution of apharmaceutically acceptable acid such as hydrochloric acid, sulphuricacid, methanesulphonic acid, fumaric acid, maleic acid, succinic acid,acetic acid, benzoic acid, oxalic acid, citric acid, tartaric acid,carbonic acid or phosphoric acid. Furthermore, where the compounds ofthe invention carry an acidic moiety, suitable pharmaceuticallyacceptable salts thereof may include alkali metal salts, e.g. sodium orpotassium salts, alkaline earth metal salts, e.g. calcium or magnesiumsalts; and salts formed with suitable organic ligands, e.g. quaternaryammonium salts. Conventional procedures for the selection andpreparation of suitable prodrug derivatives are further described in,for example, Design of Prodrugs, ed. H. Bundgaard, Elsevier, 1985.

Where the compounds according to the invention have at least oneasymmetric center, they may accordingly exist as enantiomers. Where thecompounds according to the invention possess two or more asymmetriccenters, they may additionally exist as diastereoisomers. It is to beunderstood that all such isomers and mixtures thereof in any proportionare encompassed within the scope of the present invention.

The invention also provides pharmaceutical compositions comprising oneor more compounds of this invention in association with apharmaceutically acceptable carrier. Preferably these compositions arein unit dosage forms such as tablets, pills, capsules, powders,granules, sterile parenteral solutions or suspensions, metered aerosolor liquid sprays, drops, ampoules, auto-injector devices orsuppositories; for oral, parenteral, intranasal, sublingual or rectaladministration, or for administration by inhalation or insufflation. Itis also envisioned that the compounds of the present invention may beincorporated into transdermal patches designed to deliver theappropriate amount of the drug in a continuous fashion.

For preparing solid compositions such as tablets, the principal activeingredient is mixed with a pharmaceutically acceptable carrier, e.g.conventional tableting ingredients such as corn starch, lactose,sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalciumphosphate or gums, and other pharmaceutical diluents, e.g. water, toform a solid preformulation composition containing a homogeneous mixturefor a compound of the present invention, or a pharmaceuticallyacceptable salt thereof. When referring to these preformulationcompositions as homogeneous, it is meant that the active ingredient isdispersed evenly throughout the composition so that the composition maybe easily subdivided into equally effective unit dosage forms such astablets, pills and capsules. This solid pre-formulation composition isthen subdivided into unit dosage forms of the type described abovecontaining from 0.1 to about 500 mg of the active ingredient of thepresent invention. Typical unit dosage forms contain from 1 to 100 mg,for example, 1, 2, 5, 10, 25, 50 or 100 mg, of the active ingredient.The tablets or pills of the novel composition can be coated or otherwisecompounded to provide a dosage affording the advantage of prolongedaction. For example, the tablet or pill can comprise an inner dosage andan outer dosage component, the latter being in the form of an envelopeover the former. The two components can be separated by an enteric layerwhich, serves to resist disintegration in the stomach and permits theinner component to pass intact into the duodenum or to be delayed inrelease. A variety of materials can be used for such enteric layers orcoatings, such materials including a number of polymeric acids andmixtures of polymeric acids with such materials as shellac, cetylalcohol and cellulose acetate.

The liquid forms in which the novel compositions of the presentinvention may be incorporated for administration orally or by injectioninclude aqueous solutions, suitably flavored syrups, aqueous or oilsuspensions, and flavored emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles. Suitable dispersing or suspendingagents for aqueous suspensions include synthetic and natural gums suchas tragacanth, acacia, alginate, dextran, sodium caboxymethylcellulose,methylcellulose, polyvinylpyrrolidone or gelatin.

The compounds according to the present invention exhibit schizophreniareducing/alleviating activity, as demonstrated by standard protocols.For example, efficacy of the present inventive compounds in theschizophrenia context has been demonstrated by assaying startle responseto a load stimulus (pulse) when preceded by a pre-pulse stimulus (seeExamples 2-5 herein). Accordingly, another aspect of the inventionprovides a method for the reduction of schizophrenia in a subject inneed of such treatment by administration of an effective amount ofcysteine prodrug or dimer thereof. In the treatment of schizophrenia,suitable dosage level (i.e, an effective amount) is about (1-5000)mg/kg, per day, preferably about (30-3000) mg/kg per day, and especiallyabout (50-1000) mg/kg per day. The compounds may be administered on aregimen of 1 to 4 times per day, or on a continuous basis.

As well, the compounds according to the present invention may alsoexhibit the ability to reduce drug cravings. This desirable activity canbe shown in animal models involving drug-seeking behavior produced bystress, drug-paired cues, or a cocaine priming injection. The efficacyof compounds according to the present invention are further describedin, e.g., Example 6 below. Accordingly, yet another aspect of theinvention is directed to a method of reducing a drug craving in asubject in need thereof. Such a method includes the step ofadministering an effective amount of a compound having the chemicalstructure of an inventive compound described herein to the subjectwhereby the drug craving is reduced in the subject. In the treatment ofdrug cravings, suitable dosage level (i.e., effective amount) is about(1-5000) mg/kg, per day, preferably about (30-3000) mg/kg per day, andespecially about (50-1000) mg/kg per day.

The following examples are, of course, offered for illustrative purposesonly, and are not intended to limit the scope of the present inventionin any way. Indeed, various modifications of the invention in additionto those shown and described herein will become apparent to thoseskilled in the art from the foregoing description and the followingexamples and fall within the scope of the appended claims.

EXAMPLES Example 1

Preparation of Phenylsulfenyl Chloride:

Into a three-neck, round-bottom flask (1 L), fitted with an argon inlet,a pressure-equalizing dropping funnel (500 mL), and a magnetic stir bar,was charged with thiophenol (84 mL) (Note 1), dry triethylamine (1 mL),and dry pentane (400 mL) (Note 2) under a blanket of argon. Theremaining neck of the flask was stoppered and the argon was allowed tosweep gently through the flask and out of the pressure-equalizingdropping funnel. The flask and its contents were cooled to 0° C. with anice bath and stirring was begun. The dropping funnel was charged withsulfuryl chloride (76 mL) (Note 1). The sulfuryl chloride was addeddropwise over a 1-hr period to the chilled thiophenol solution withstirring. During this addition, a thick layer of white solid formed. Itgradually dissolved as it was broken apart. After the addition wascomplete, the ice bath was removed and the mixture was allowed to stirfor 1 h longer while slowly warming to room temperature. During thecourse of the addition and subsequent stirring, the clear, pale-yellowsolution became dark orange-red. The dropping funnel was replaced withan outlet adapter connected to a vacuum pump and the argon inlet wasexchanged for a ground glass stopper. The pentane and excess sulfurylchloride were removed under reduced pressure at room temperature. Afterthis, the outlet adapter was replaced by a short-path distillationapparatus adapted for use under reduced pressure. The oily red residuewas distilled to give phenylsulfenyl chloride as a blood-red liquid (26g, 87%), by 41-42° C. (1.5 mm) (Note 3). This compound was stored underargon until used in Part B (Note 4).

Note 1. Thiophenol (97%) and sulfuryl chloride (97%) were obtained fromAldrich Chemical Company, Inc. and used without further purification.

Note 2. Both pentane and triethylamine were obtained from the AldrichChemical Company, Inc. Before use they were dried over sodium wire anddistilled from fresh sodium wire onto Linde 4A molecular sieves under anatmosphere of argon.

Note 3. Yields of phenysulfenyl chloride of 82-92% were obtained.

L-Alanine, 3-(phenyldithio)-(1a)

To a solution of L-cysteine hydrochloride monohydrate (47 g, 0.3 mol) inabsolute ethanol (900 mL) was added powdered sodium bicarbonate (30 g,0.36 mol) at 0° C. in one portion. Phenylsulfenyl chloride (50 g, 0.345mol) was added dropwise with stirring to the mixture. After the completeaddition of the reagent, the reaction mixture was allowed to stand atroom temperature and the sodium chloride which was produced during thereaction was removed by filtration. After basifying the mixture by theaddition of pyridine (38 mL) into the filtrate, the fine precipitatewhich formed was allowed to stand for a couple of hours, then filtratedand washed well with ethanol and dried to provide the crude product as awhite solid. After recrystallization from aqueous HCl (0.5 N, 4000 mL),the final product S-thiol-phenyl-L-cysteine 1a was obtained (52 g) in76% yield as colorless plates. m.p. 192° C. (decomp). ¹H NMR (CD₃CO₂D):δ 3.53-3.76 (m, 2H), 4.89 (t, 1H), 7.26-7.88 (m, 5H); ¹³C NMR (75.5 MHz,CD₃CO₂D): δ 35.5, 52.5, 127.6, 128.5, 129.1, 129.3, 133.5, 171.6. Thismaterial was employed directly in the next step.

2,5-Oxazolidinedione, 4-[(phenyldithio)methyl]-(2a)

To a rapidly stirred (overhead stirrer) suspension ofS-thiol-phenyl-L-cysteine 1a (57.5 g, 0.25 mol) in THF (250 mL) wasadded solid triphosgene (26 g, 88 mmol) in one portion at 45-50° C.(before addition, remove the heating mantle). When the temperature dropsto 45° C., put the heating mantle back on and maintain the insidetemperature around 45-50° C. until the solution becomes homogeneous.After the removal of the heating mantle, the solution was purged withargon overnight into a NaOH bubbler to remove any residual phosgene. Thesolvent was evaporated in vacuo and this provided anhydride 2a (55 g) in85% yield: m.p. 217° C. (decomp). ¹H NMR (CDCl₃) δ 2.90-2.98 (m, 1H),3.30 (d, 1H, J=12 Hz), 4.68 (d, 1H, J=9 Hz), 6.01 (s, 1H), 7.34-7.58 (m,5 H); ¹³C NMR (75.5 MHz, CD₃CO₂D): δ 39.4, 56.5, 128.3, 128.9, 129.5,135.2, 150.8, 167.7. Due to the unstable nature of this anhydride, itwas stored in the refrigerator overnight under an atmosphere of argonand used immediately the next day without further purification.

2,5-piperazinedione, 3-(mercaptomethyl)-(4)

A solution of the N-carboxyanhydride 2a (35.7 g, 0.14 mol) in THF (160mL) was added dropwise to a vigorously stirred (overhead stirrer)mixture of glycine ethyl ester hydrochloride (28 g, 0.16 mol), freshlydistilled triethylamine (20.4 g, ˜28 mL, 0.20 mol) and dry chloroform(240 mL) at −78° C. in a three-neck flask (2 L). The reaction mixturewas allowed to warm to 0° C. over 8 h, and then was stirred at rt for 12h, after which the reaction solution was filtered to remove thetriethylamine hydrochloride which precipitated. The filtrate was thenconcentrated under reduced pressure (<40° C.) and the crude dipeptideester was used for the preparation of the diketopiperazine 4 withoutfurther purification. ¹H NMR (CDCl₃): δ 1.29 (t, 3H), 1.93 (br, 2H),2.74-2.82 (m, 1H), 3.40 (dd, 1H), 3.73 (dd, 1H), 4.03-4.19 (m, 2H),4.19-4.26 (m, 2H), 7.34-7.58 (m, 5H).

b). The crude dipeptide ester (37.6 g, 0.12 mol) was heated in refluxingtoluene (1000 mL) for 12 h and then cooled down to rt and kept at 0° C.for 16 h. The bislactam 4 which precipitated was isolated by vacuumfiltration, washed with ether (3×150 mL), and dried under vacuum at 100°C. to provide pure diketopiperazine 4 (10.0 g) in 45% yield. Theresulting filtrate produced from washing the desired diketopiperazinewas evaporated under vacuum and toluene (800 mL) was added to theresidue. The toluene solution was heated at reflux for another 40 h(under argon) and then the above steps were repeated to collect another5-8 grams of diketopiperazine 4 (combined yield, 73%). 4: m.p. 258° C.¹H NMR (DMSO-d₆): δ 3.09-3.26 (m, 2H), 3.68-3.88 (m, 2H), 4.10 (s, 1H),8.17 (s, 1H), 8.19 (s, 1H); ¹³C NMR (500 MHz, DMSO-d₆): δ 43.5, 44.7,54.3, 166.2, 166.6; MS (EI) m/e (relative intensity) 160(M⁺+1, 12),140(5), 126(72), 114(100), 97(20), 85(30).

3-Phenyldisulfanylmethyl-piperazine-2,5-dione (3a)

c). The solution which resulted from step b above was cooled to 0° C.and keep at 0° C. for 12 h. The precipitate which resulted was filteredand provided phenyl-thiol analog 3a in 30% yield. 3a: ¹H NMR (DMSO-d₆):δ 3.09-3.21 (m, 2H), 3.65-3.82 (m, 2H), 4.10 (s, 1H), 7.11-7.55 (m, 5H),8.18 (s, 1H), 8.20 (s, 1H); ¹³C NMR (75.5 MHz, DMSO-d₆): δ 43.5, 47.8,54.2, 125.6, 127.7, 128.2, 129.5, 166.2, 166.6; MS (EI) m/e (relativeintensity) 268 (M⁺+1, 55), 250(35), 218(68), 159(66), 141(80), 126(70).

(3,6-Diethoxy-2,5-dihydro-pyrazin-2-yl)-methanethiol (5) TriethyloxoniumTetrafluoroborate

(Note: Triethyloxonium tetrafluoroborate is an expensive reagent;however, it is relatively easy to prepare even on large scale). Athree-neck flask (500 mL), pressure equilibrating dropping funnel (125mL) and a condenser were dried in an oven at 150° C. and assembled whilehot under an atmosphere of argon. When the equipment had cooled to rt,ether [(100 mL) which had been previously dried over sodium benzophenoneketyl] and boron trifluoride diethyletherate (91 g, ˜87 mL, 64 mmol)were combined [Note: On this scale the colorless BF₃ etherate wasobtained from a freshly opened new bottle. If the reagent was slightlyyellow or if the reaction was scaled down, the BF₃ etherate needed to bevacuum distilled first]. The ethereal solution which resulted was heatedto a gentle reflux after which dry epichlorohydrin (48.8 g, ˜41 mL, 51.8mmol) was added dropwise over 1 h. The mixture was heated at reflux foran additional 1 h and allowed to stand at rt (under argon) overnight.The ether was removed by applying a positive pressure of argon in oneneck of the flask while forcing the ether out through a filter stick(fritted glass tube) inserted into another neck of the flask and into acollection flask. The slightly yellow solid which remained in the flaskwas rinsed twice in the same manner with anhydrous ether (3×50 mL) toprovide a crystalline white solid. The solid was not weighed butdirectly used in the next step. The following sequence was based on theyield of this reaction process at the level of 80-85%.

Dry CH₂Cl₂ (100 mL) was added to the flask (500 mL) which contained thefreshly prepared triethyloxonium tetrafluoroborate (˜42 g, 336 mmol)from the previous reaction (under argon). To this solution was added thediketopiperazine 4 (5 g, 31.2 mmol) in portions with stirring (overheadstirrer). After 2 h the reaction mixture became homogenous. The solutionwas stirred at rt under argon for 72 h after which the mixture was addedvia a cannula to an aq solution of NH₄OH (14%, 100 mL) mixed with ice(100 g). The organic layer was washed with a saturated aq solution ofNaHCO₃ (2×50 mL) and brine (80 mL) after which it was dried (K₂CO₃).After filtration the solvent was removed under reduced pressure toprovide the bis-ethoxy lactim ether 5 as a clear yellow liquid that wasfurther purified by flash chromatography (EtOAc:Hexane=1:4) in 71% yield(4.8 g, 22 mmol). 5: [α]_(D) ²⁶=+52.2° (c=2.5, CHCl₃). ¹H NMR (CDCl₃) δ1.32-1.36 (m, 6H), 3.27-3.30 (m, 3H), 4.08-4.22 (m, 6H), 4.39 (s, 1H);¹³C NMR (75.5 MHz, CDCl₃): δ 14.7, 46.3, 47.5, 56.1, 61.5, 61.6, 162.7,163.6; HRMS (ESI), cat. (M+H)⁺: 217.2982; found: 217.2990. [Note:Previous reports employ an aq solution of Na₂HPO₄.2H₂O instead of theabove aq NH₄OH in the workup stages of the reaction sequence. The abovereaction scale (100 g of bis-lactim 5) would, however, require over 1 kgof Na₂HPO₄.2H₂O and 5 L of water according to that procedure,consequently, the present procedure employing a mixture of ice and aq(14%) NH₄OH (2 L total) was developed for simplicity].

Bis[(3,6-Diethoxy-2,5-dihydro-pyrazin-2-yl)-methanethiol] (6)

To the bis-ethoxy lactim ether 5 (400 mg, 1.85 mmol) in dry EtOH (10 mL)was added a catalytic amount of I₂ (50 mg, 10% mmol) at rt. The mixturewas stirred for 6˜12 h under air until analysis (TLC, silica gel)indicated the reaction was complete (new spot appeared under S.M. on theTLC plate). The organic solvent was evaporated under reduced pressure.The mixture which resulted was dissolved into EtOAc (20 mL), washed withsat. sodium thiosulfate (5˜10 mL) and dried (Na₂SO₄). The solvent wasthen removed under reduced pressure which provided the dimer 6: ¹H NMR(CDCl₃) δ 1.32-1.36 (m, 6H), 3.27-3.30 (m, 3H), 4.08-4.22 (m, 6H), 4.39(s, 1H); ¹³C NMR (75.5 MHz, CDCl₃): δ 14.7, 46.3, 47.5, 56.1, 61.5,61.6, 162.7, 163.6; The NMR spectra was identical to its monomer exceptthe S—H bond had disappeared. HRMS (ESI) cat. (M+H)⁺: 431.1787; found:431.1790.

2-Amino-3-tritylsulfanyl-propionic acid (S-Trityl-L-cysteine) (1b)

L-Cysteine hydrochloride (100 g, 0.634 mol) and trityl chloride (270 g,0.969 mol) were stirred in DMF (400 mL) for 2 days at room temperature.A 10% sodium acetate solution (3.5 L) was then added dropwise and thewhite precipitate which formed was filtered and washed with distilledwater. Afterward, the residue was stirred in acetone at 50° C. for 30min after which it was cooled to 0° C. and filtered. The precipitate waswashed with a little acetone and diethyl ether and dried in vacuo.S-Trityl-L-cysteine 1b (205 g, 89%) was obtained as a white powder. 1b:m.p. 192° C. (decomp). ¹H NMR (DMSO-d₆) δ 2.45 (dd, 1H, J=9 Hz, 12 Hz),2.58 (dd, 1H, J=4.4 Hz, 12 Hz), 2.91 (m, 1H), 7.22-7.36 (m, 15H); ¹³CNMR (75.5 MHz, DMSO-d₆): δ 33.8, 53.7, 66.4, 127.1, 127.8, 128.1, 128.4,129.5, 144.5, 168.4. This material was directly used in the next stepwithout further purification.

4-Tritylsulfanylmethyl-oxazolidine-2,5-dione (2b) was prepared followingthe procedure for preparation of 2a as a brown oil in 85% yield. 2b: ¹HNMR (CDCl₃) δ 2.70-2.85 (m, 2H), 3.47-3.56 (m, 1H), 5.62 (s, 1H),7.07-7.73 (m, 15H). This material was directly used in the next stepwithout further purification.

3-Tritylsulfanylmethyl-piperazine-2,5-dione (3b) was prepared followingthe procedure for preparation of 3a. 3b: m.p. 225-227° C. [α]_(D)²⁶=+7.8° (c=1.05, CHCl₃). ¹H NMR (CDCl₃) δ 2.73-2.91 (m, 2H), 3.12 (d,1H, J=12.3 Hz), 3.95 (s, 1H), 5.80 (s, 1H), 5.82 (s, 1H), 7.20-7.62 (m,15H). ¹³C NMR (75.5 MHz, CDCl₃): δ 35.9, 44.8, 53.0, 126.9, 128.1,129.4, 144.0, 166.6. This material was directly used in the next stepwithout further purification.

Bis[2,5-Piperazinedione, 3-(mercaptomethyl)-] (7)

The trityl protected diketopiperazine 3b (1.5 g, 3.73 mmol) wasdissolved in a solution of methylene chloride (20 mL) and methanol (40mL) with stirring. Pyridine (1.2 mL, 15 mmol) was then added to theresulting mixture, followed by a solution of iodine (0.97 g, 3.8 mmol)in methanol (5 mL). The mixture was allowed to stir for 1 h at roomtemperature. No precipitate had formed by this time; however, TLCanalysis indicated that the reaction was proceeding slowly by theappearance of a new spot under the starting material (UV light). Aprecipitate began to form within 2 h after concentrating the solution toa volume of 10 mL and methanol (30 mL) was added to result in a totalvolume of 40 mL. The solution was stirred an additional 23 h and theprecipitate was filtered off. The solid was washed with cold methanoland then decolorized by shaking with 10% aqueous sodium bisulfite (10mL). The precipitate was filtered and dried to yield dimer 7 as whitesolid (680 mg, 57%). 7: m.p. >300° C. ¹H NMR (DMSO-d₆) δ 3.11-3.21 (m,2H), 3.70 (d, 1H, J=0.96 Hz), 3.73 (d, 1H, J=0.99 Hz), 4.11 (s, 1H),8.17 (s, 1H), 8.19 (s, 1H); ¹³C NMR (75.5 MHz, DMSO-d₆): δ 44.0, 45.2,54.8, 166.7, 167.1; HRMS (ESI) cat. (M+H)⁺: 319.0535; found 319.0533.

Example 2 Compound 7 (Scheme 1) Produces a Larger Increase in Glutamatein the Prefrontal Cortex Relative to NAC

FIG. 1 is a bar graph depicting extracellular glutamate in theprefrontal cortex (compared to baseline) following administration ofcysteine prodrugs N-acetylcysteine (60 mg/kg, IP; N=4) or compound 7 (30mg/kg, po; N=1) in rats. These results indicate a much larger peakincrease in glutamate was obtained for compound 7 relative toN-acetylcysteine. Compound 7 was given to the animal orally, and therebysubjected to potential first-pass metabolism. Conversely,N-acetylcysteine was given IP in order to avoid extensive first passmetabolism that would occur following oral administration. Thus,compound 7 produced a larger relative increase in glutamate in rats ascompared to NAC even though NAC was given in its preferred route ofadministration and at twice the concentration. This increased glutamatelevel indicates that compound 7 is successful in elevating extracellularcystine levels and driving cystine-glutamate exchange, a phenomenonunderstood to be beneficial in overcoming schizophrenia and/or drugaddiction.

Example 3 Efficacy of Compound 7 (Scheme 1) as a Novel AntipsychoticAgent

FIG. 2 is a bar graph illustrating inhibition of a startle response inresponse to a load stimulus (pulse) when preceded by a pre-pulsestimulus (2-15 db above background). Prepulse inhibition is a commonlyused paradigm to screen antipsychotic agents for use in treatingschizophrenia. The pre-pulse stimulus in the present study reduced thestartle response in saline controls (N=5) by >60% relative to theresponse elicited following exposure to the pulse only. Rats pretreatedwith phencyclidine only (PCP; 1 mg/kg, SC; N=5) failed to exhibit areduction in the response elicited by the pulse even when preceded bythe pre-pulse. This reflects sensorimotor gating deficits common topatients afflicted with schizophrenia. Rats pretreated withN-acetylcysteine (30 mg/kg, po; N=5) 60 min prior to phencyclidineadministration exhibited a trend toward improved sensorimotor gating(p=0.1). Rats pretreated with compound 7 (30 mg/kg, po; N=4) exhibited asignificant improvement in sensorimotor gating relative to PCP controlsand rats receiving NAC+PCP (Fisher LSD, p<0.05). Collectively, thesedata indicate efficacy of compound 7 as a novel antipsychotic thatexceeds the potential of N-acetylcysteine.

Example 4 N-acetylcysteine & PCP-Induced Deficits in Prepulse Inhibition

The following data set illustrate the present drawbacks associated withN-acetylcysteine, specifically the extensive hepatic metabolism and poorblood brain permeability. FIG. 3 depicts the impact of N-acetylcysteineadministered orally on deficits in prepulse inhibition produced byphencyclidine. As described below, deficits in prepulse inhibitionfollowing administration of phencyclidine represent one of the mostcommon preclinical paradigms used to screen potential antipsychoticagents. Oral administration of N-acetylcysteine (administered 60 minprior to testing; N=7-10/group), which is subjected to hepaticmetabolism, fails to significantly attenuate deficits in prepulseinhibition produced by phencyclidine (0 NAC+PCP).

The data depicted in the FIG. 4 illustrate the impact ofN-acetylcysteine (n=5-6/group; injected 60 min prior to testing) whenadministered into the intraperitoneal cavity in order to circumventhepatic metabolism. N-acetylcysteine failed to significantly restoresensorimotor gating at any of the three prepulse stimulus intensities,likely a result of poor blood brain permeability.

FIG. 5 depicts the impact of N-acetylcysteine infused directly into therodent prefrontal cortex, the region thought to underlie sensorimotorgating. Direct infusion of N-acetylcysteine (0-100 microM) circumventsthe pharmacokinetic aspects of N-acetylcysteine that mitigate its use asa pharmacotherapy for schizophrenia, including extensive hepaticmetabolism and poor blood brain permeability. As indicated in FIG. 5,infusion of N-acetylcysteine into the prefrontal cortex significantlyrestored inhibition of a startle response at each concentration tested(N=6-8/group; * indicates a significant increase relative to PCP ratsreceiving 0 NAC, Fisher LSD, P<0.05). Note, N-acetylcysteine-inducedreversal of the effects of PCP compare favorably to the effect ofclozapine, arguably the most effect antipsychotic on the market.

Example 5 Efficacy of Compounds 5 and 6 (Scheme 1) as NovelAntipsychotic Agents

Startle chambers (Kinder Scientific; 10.875″×14″×19.5″) utilized for allexperiments were housed in a sound attenuating chamber and mounted to amotion sensing plate. During all sessions, the background noise was heldconstant at 60 dB by presenting white noise through a speaker mountedabove the animal. Rats underwent a 5-min habituation session prior toall matching and test sessions. Matching sessions were used to determinethe magnitude of each rat's startle response to a loud auditory stimulus(pulse; 50 dB above background; 20 ms), which was assessed following thepresentation of seventeen pulse stimuli (50 dB above background)presented alone and three pulse stimuli (50 dB above background)preceded by a mild auditory stimulus (prepulse; 12 dB above background;20 ms). Rats were then assigned to treatment groups such that themagnitude of the startle response was equivalent across all groups. Testsessions consisted of 60 trials, 28 in which the pulse stimulus waspresented alone (Pulse), 24 trials in which the pulse stimulus waspreceded (100 ms) by a mild auditory stimulus (Prepulse; 2, 6, 15 dBabove background), and 8 silent trials (No stim; background noise only).The percent prepulse inhibition was calculated as the magnitude of thestartle response when the pulse was preceded by prepulse stimuli dividedby the magnitude of the startle response when only the pulse stimulus ispresented (×100).

Prior to testing, rats received a cysteine prodrug (0-1 mg/kg, p.o.;N=9-15/group) and 50 min later an injection of PCP (0-1.25 mg/kg, SC).Ten minutes later, rats underwent the test session as described above.The novel cysteine prodrug 5, described in Scheme 1, administered orallyto rodents 60 min prior to testing at a dose of 1 mg/kg produced asignificant increase in sensorimotor gating as assessed by inhibition ofa startle response as shown in FIG. 6 (* indicates a significantincrease relative to PCP rats receiving no cysteine prodrug, Fisher LSD,P<0.05). Note, these data compare quite favorably to the resultsobtained with oral administration of N-acetylcysteine.

The data depicted in the FIG. 7 were collected as described above,except compound 6 described in Scheme 1 was administered 60 min prior totesting (N=9-11/group). As the data demonstrate, oral administration ofcystine dimer 6 significantly restored sensorimotor gating at thehighest prepulse intensity.

Example 6 Efficacy of Compound 5 (Scheme 1) as Novel Anticraving Agent

The extinction/reinstatement paradigm represents one of the most commonparadigms used to screen for potential anticraving properties of novelpharmacotherapies. In the present experiments, rats were implanted withindwelling jugular catheters with an external port affixed slightlyposterior to the rat's shoulder blades. Tubing is used to connect asyringe of cocaine to the external port of the indwelling catheter. Ratsare then placed into standard operant chambers (Med Associates) andpermitted to press a lever for an infusion of cocaine (0.5 mg/kg/200microL, IV). Once behavior is stable, rats are permitted at least eleven2-hr sessions to self-administer cocaine. Afterwards, the cocainesolution is replaced with saline in order to extinguish lever pressing.Once responding decreases to 10 or fewer lever presses/2 hr sessions for3 out of 4 daily sessions, rats are tested for reinstatement (relapse).To do this, rats are placed into the operant chamber and vehicle or acysteine/cystine prodrug (1-60 mg/kg, p.o.; N=2-12) is administered.Afterwards, rats then receive an injection of cocaine (10 mg/kg, IP).Responding is then assessed for 120 min. Data depicted in FIG. 8illustrate that N-acetylcysteine (IP) is effective in producing asignificant reduction in cocaine-induced reinstatement at the doses of30 and 60 mg/kg (IP; * indicates a significant decrease in respondingrelative to rats treated with 0 NAC, Fisher LSD). FIG. 9 demonstratesthat N-acetylcysteine is less effective when given orally. Further,administration of 1 mg/kg of Compound 5 (Scheme 1) was sufficient toblock cocaine-induced reinstatement, an effect that was comparable to 30mg/kg NAC (* indicates a significant decrease in responding relative torats treated with 0 NAC, Fisher LSD).

While this invention has been described in conjunction with the variousexemplary embodiments outlined above, various alternatives,modifications, variations, improvements and/or substantial equivalents,whether known or that are or may be presently unforeseen, may becomeapparent to those having at least ordinary skill in the art.Accordingly, the exemplary embodiments according to this invention, asset forth above, are intended to be illustrative, not limiting. Variouschanges may be made without departing from the spirit and scope of theinvention. Therefore, the invention is intended to embrace all known orlater-developed alternatives, modifications, variations, improvements,and/or substantial equivalents of these exemplary embodiments. Alltechnical publications, patents and published patent applications citedherein are hereby incorporated by reference in their entirety for allpurposes.

1. A cysteine prodrug having the structure:

a cystine dimer of said prodrug having the structure:

wherein: R¹, R², R⁴ and R⁵ are independently selected from OH, ═O, or abranched or straight chain C₁ to C₅ alkoxyl group, with the caveats thatwhen ═O is selected the nitrogen atom adjacent the carbonyl group thuslyformed bears a H and a single bond joins the adjacent nitrogen to saidcarbonyl group and further R¹, R², R⁴ and R⁵ shall be selected to notall be ═O; and R³ is H, a branched or straight chain C₁ to C₅ alkyl, anitrobenzenesulfonyl, an aryl thio, an aryl, an alkylthio, an acyl, abenzoyl, a thio acyl, a thio benzoyl, or a benzyl group.
 2. The cysteineprodrug according to claim 1, wherein said prodrug has the structure:


3. The cysteine prodrug according to claim 1, wherein said prodrug isthe cystine dimer having the structure:


4. The cysteine prodrug according to claim 1, wherein R¹, R², R⁴ and R⁵are independently selected from the branched or straight chain C₁ to C₅alkoxyl group.
 5. The cysteine prodrug according to claim 1, wherein R¹,R², R⁴ and R⁵ are selected from the same branched or straight chain C₁to C₅ alkoxyl group.
 6. A pharmaceutical composition comprising acysteine prodrug or dimer thereof according to claim 1 and apharmaceutically-acceptable carrier.
 7. A method of reducing drugcraving in a subject comprising administering to said subject aneffective amount of a prodrug or dimer thereof according to claim 1,whereby drug craving is reduced in said subject.
 8. The method accordingto claim 7, wherein said prodrug has the structure:


9. The method according to claim 7, wherein said prodrug is the cystinedimer having the structure:


10. The method according to claim 7, wherein the step of administeringto said subject is accomplished by oral delivery.
 11. A method ofreducing drug craving in a subject comprising administering to saidsubject an effective amount of a cysteine prodrug having the structure:

a cystine dimer of said prodrug having the structure:

wherein R is H, a branched or straight chain C₁ to C₅ alkyl, anitrobenzenesulfonyl, an aryl thio, an aryl, an alkylthio, an acyl, abenzoyl, a thio acyl, a thio benzoyl, or a benzyl group, whereby drugcraving is reduced in said subject.
 12. The method according to claim11, wherein the cysteine prodrug has the structure:


13. The method according to claim 11, wherein the step of administeringto said subject is accomplished by oral delivery.